2f1o

Crystal Structure of NQO1 with Dicoumarol
(see also NADH quinone oxidoreductase (NQO1) with inhibitor dicoumarol)



NAD(P)H quinone oxidoreductase 1 (NQO1, EC 1.6.5.2) is a ubiquitous flavoenzyme that catalyzes two electron reduction of quinones to hydroquinones utilizing NAD(P)H as an electron donor. The crystal structure of human NQO1 in complex with dicoumarol was determined at 2.75 Å resolution. NQO1 is a physiological homodimer composed of two interlocked monomers. Two catalytic sites are formed and are present at the dimer interface (FAD is colored red and dicoumarol is colored blue ). Therefore, each from these two dicoumarol-hNQO1 binding sites is formed by both monomers. Dicoumarol is colored cyan, FAD in orange , nitrogens and oxygens are shown in CPK colors. NQO1 chain A is colored blueviolet and chain C in lime. NQO1 residues, participating in ligand interactions, are shown as stick representation and are labeled (A and C refer to the NQO1 chains). H-bonds are shown by dashed lines with their distances.

Superposition of the active site of dicoumarol/hNQO1 complex (residues important for ligand interactions are in stick representation and colored magenta ) with the apo hNQO1 (1d4a, residues important for ligand interactions are colored blue ). Dicoumarol is colored in cyan ; <font color='orange'>FAD is colored in orange. The RMSD between the apo hNQO1 (1d4a) and hNQO1 in complex with dicoumarol is 0.36Å for the 546 Cα atoms. The dicoumarol-hNQO1 binding causes several structural changes. The most prominent of them is Tyr 128 and Phe 232 movement in the first monomer. These residues are located on the surface of the NQO1 catalytic pocket. The <scene name='2f1o/Align/9'>distance between these residues increases from ~5 Å in the <font color='blue'>apo hNQO1 to ~12 Å in the <font color='magenta'>dicoumarol/hNQO1 complex. Quinones (including duroquinone (2,3,5,6-tetramethyl-p-benzoquinone) are substrates of NQO1 (it catalyzes two-electron reduction of them to hydroquinones). Duroquinone <font color='black'>(yellow) binds to the <scene name='2f1o/Align1/4'>active site by interactions involving the FAD and several hydrophobic and hydrophilic residues in the duroquinone-NQO1 complex (1dxo). The structure of the hNQO1 dimer in complex with duroquinone is also similar to that of hNQO1 in complex with dicoumarol (RMSD is 0.33Å for the 546 Cα atoms). In this case, the main differences between these two structures, as well as to that of apo hNQO1, involve the distance between residues <scene name='2f1o/Align1/5'>Tyr 128 and Phe 232 of the first monomer. The FAD molecule has very similar conformation in both hNQO1-duroquinone <font color='pink'>(pink) and hNQO1−dicoumarol <font color='orange'>(orange) complexes.

The quinone ES936 causes irreversible inhibition of the NQO1. <scene name='2f1o/Align2/5'>Alignment of the hNQO1 dimer in complex with <font color='red'>ES936 (red) (1kbq) with the hNQO1−dicoumarol complex yields 0.45Å RMSD for the 546 Cα atoms. The ES936 causes structural change only in the position of Phe 232. The movement of this residue is smaller than that caused by dicoumarol. The <scene name='2f1o/Align2/6'>distance between Tyr 128 and Phe 232 in the hNQO1−ES936 complex is only ~7 Å, while in the hNQO1−dicoumarol complex it is ~12 Å. </StructureSection>

About this Structure
2F1O is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference
The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol., Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y, Biochemistry. 2006 May 23;45(20):6372-8. PMID:16700548

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